InvestorsHub Logo
Followers 72
Posts 4827
Boards Moderated 0
Alias Born 01/24/2004

Re: cjgaddy post# 68683

Monday, 09/26/2011 9:45:03 AM

Monday, September 26, 2011 9:45:03 AM

Post# of 345554
Peregrine’s Bavi+Riba/HCV(geno1) trial (enroll.comp 9-26-11) – designed to help determine if Bavi will become “a potential alternative to (current) Interferon-based regimens” in HCV combo therapies…

Recall Peregrine’s CEO Steve King’s 1-10-2011 comments about the new randomized Bavi+Riba HCV Ph.2 Trial:
"Our 4th randomized Ph.2 trial evaluating bavituximab for oncology & viral infections is designed to build on our 3 prior Phase I HCV trials, which have demonstrated our antibody's acceptable safety & promising signs of antiviral activity. Although there are several targeted antiviral drug candidates in development against HCV, immune stimulation with interferon remains a cornerstone of the standard HCV regimen, but unfortunately causes serious side effects and unacceptable toxicity for many patients. With bavituximab's immune reactivation mechanisms and safety profile to date, we are eager to assess this new combination as a potential alternative to interferon-based regimens for patients infected with HCV."
1-10-11 PR: http://tinyurl.com/2g7rdp
http://clinicaltrials.gov/ct2/show/NCT01273948

As well at his (SK’s) comments on Bavi+Riba/HCV from the 9-9-2011 CC:
SK 9-9-11, Q&A(Roger Adams): “For the HCV program, if we have positive data and it validates the potential of bavituximab as an immunotherapy in HCV, then that's a program that we might want to just outright license to someone because it's a specialty area, it's an ever-evolving area, and it's a type of indication where a partner wants to customize it for their particular portfolio products in that area.”
http://tinyurl.com/3bx8eat

And, most interesting…
7-11-2011 ‘Nature Biotechnology’ HCV article includes Bavituximab in table of 18 “Selected HCV Drugs In Development”, and quotes Dr. Philip Thorpe in a paragraph discussing Peregrine’s efforts to dispense with IFN-A by subverting a mechanism that enables viruses to evade the immune response.”
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=65297209
TABLE 1 - SELECTED HCV DRUGS IN DEVELOPMENT [Nature Biotechnology, 7-11-2011]

ARTICLE EXTRACTS [Nature Biotechnology, 7-11-2011]:
The recent, near-simultaneous US FDA approvals of the viral protease inhibitors Victrelis (boceprevir) and Incivek (telaprevir = VX-950) developed, respectively, by Merck & Vertex, for treating hepatitis C virus (HCV) infection, represent genuine progress in an area poorly served by existing therapy. But these new therapies, approved in May, are not likely to remain in pole position for very long. Numerous other molecules in development based on various other mechanisms (Table 1) offer more tolerable alternatives. . . But the newly approved drugs also have major shortcomings, adding an extra safety & toxicity burden to a treatment that is already difficult to take.
. . .
Eliminating IFN-A [interferon-alpha] altogether from triple treatments is another major theme. “It is quite a toxic treatment, and people suffer under that drug,” says Philip Thorpe, professor of pharmacology at the Univ. of Texas Southwestern Medical Center, in Dallas, who is also scientific founder of Tustin, California–based Peregrine Pharmaceuticals. Peregrine is trying to dispense with IFN-A by subverting a mechanism that enables viruses to evade the immune response. The company uses bavituximab, a humanized monoclonal antibody that targets phosphatidylserine, an immunosuppressive phospholipid found on the interior of mammalian cell membranes, whose normal function is to allow apoptosis to proceed without provoking an immune response. Phosphatidylserine is ‘flipped’ to the exterior of cells that become virally infected, however, and it is also embedded on the surface envelopes of budding viruses. When thus exposed it exerts an immunosuppressive effect. “We’re hoping that if we break the apoptotic mimicry of the HCV, we’ll enhance its immunogenicity.”

= = = = = = = = = = = = = = = =
Here are some notes (updated) that I made several years back on PPHM’s positioning of Bavi as a potential IFN-replacement in HCV Combo drug therapies. If you see any errors what follows, let me know and I’ll fix & repost…
= = = = = = = = = = = = = = = =

It’s gonna take combo-therapy to whip HCV anytime in the foreseeable future. Given the current state of Direct-AV’s and Immune-Stimulators (aka “Immunomodulators”), the best of either class ALONE can’t solve the problem.

Take Vertex’s Telaprevir (VX-950) for example. Here’s what it did in a repeat-dose monotherapy Ph.1B trial (5-17-05 PR):
After 750 mg x 3 times a day x 14 days = 31,500mg of VX-950:
• Median reduction in HCV-RNA after 14 days treatment [42 doses] was [a very impressive] 4.4 log10.
• Following completion of the 14-day dosing period a slow increase in HCV-RNA levels was observed during a 28-day post-dosing period in these patients.
28 days after receiving their last dose of VX-950, there were 2 patients [of 24] that had viral levels of more than 1 log10 below their pre-treatment levels.
http://www.prnewswire.co.uk/cgi/news/release?id=146300

That’s not a negative against Telaprevir/VX950. It just confirms that Telaprevir’s ultimate role is to be combined with an effective immunotherapeutic to get those SVR’s to HOLD. Same thing with curr. SOC Ribavirin & Merck’s Boceprevir (SCH503034), and the other in-dev. “direct anti-virals”. They need to be combined with immuno-stimulatory agents to improve efficacy and increase the % of SVR’s that HOLD.

WEDMD’S DANIEL DENOON EXPLAINED IT THIS WAY ON 5-26-10:
“Because the HepC virus (HCV) rapidly becomes resistant to Telaprevir, the drug must be given in combination with other antiviral treatments, and these treatments are continued for weeks after completion of telaprevir therapy. …HCV genotype 1 is the most common U.S. strain, and the hardest to cure. Without Telaprevir, less than half of patients with genotype 1 HCV achieve a cure. In the world of HepC treatment, "cure" is a relative term. Treatment does not necessarily eradicate the virus from the body. Successful treatment results in "sustained viral response (SVR)" or "viral cure," meaning that treatment has brought the virus to undetectable levels. Usually, the immune system is able to keep any remaining HCV under control after a viral cure. About 9% of Telaprevir-treated patients who achieved SVR relapsed -- that is, their HCV levels once again became detectable during post-treatment follow-up.”
http://www.webmd.com/hepatitis/news/20100526/hepatitis-c-drug-telaprevir-ups-cure-rate

WEDMD’S DANIEL DENOON FURTHER DISCUSSED THE PROBLEM HERE ON 8-9-10:
“Boceprevir & Telaprevir each inhibit the HCV protease molecule… these HCV protease inhibitors are extremely effective at suppressing the virus they target. Unfortunately, there's another similarity. Like the AIDS virus, the hepatitis virus quickly develops resistance to protease inhibitors. Neither Boceprevir nor Telaprevir can be given alone -- each must be added to std. combination treatment with alpha interferon & ribavirin. That std. combination causes a lot of hard-to-tolerate side effects. Both Boceprevir & Telaprevir add to the side effect burden. Very preliminary evidence suggests that Boceprevir may be somewhat easier to take… And even with the improved [Boceprevir] success rate, at least 1 in 4 patients won't be cured by the new 3-drug combination [Boce+PegIFN+Riba]. In an editorial accompanying the Kwo study, Laura Milazzo & Spinello Antinori of the Univ. of Milan, Italy, note that new drugs -- in new combinations -- will be needed.”
http://www.webmd.com/hepatitis/news/20100809/boceprevir-ups-hepatitis-c-treatment-success

That’s why the industry has been attacking HCV with combo-therapies that combine viral replication inhibitors (like Telaprevir & Boceprevir), that are able to beat the viral load down fast, with a drug (presently Inteferon) that simulates the immune system, which further drives down viral load and gives us a higher percentage of permanent SVR’s that we all seek.

Which is exactly what Peregrine is going after with their Jan’11-initiated Bavi+Riba vs. PegIFN+Riba randomized Ph.2 HepC trial (see http://tinyurl.com/4uz97tv & http://clinicaltrials.gov/ct2/show/NCT01273948 ). Can Bavi replace Interferon as the preferred immune-stimulator in combo HCV treatment regimens, whether the direct-AV be Riba, Tela, or Boce, or YYYY, or ZZZZ?

Be aware that Bavituximab has always been positioned in the combo HCV therapeutic arena. This is what Peregrine CEO Steve King said on 10-24-05:
“One of the most exciting things about Bavituximab is its unique method of action. If you look at most anti-viral agents, they effectively work by blocking the replication of the virus, which is one part of the virus life cycle. If you were able to combine these agents that block viral replication with Bavituximab, which will bind to the viral particles, alerting the immune system that those viral particles need to me removed or destroyed, and in combination with binding to and hopefully destroying the target cells which are making new virus, this would be the perfect kind of 1-2 punch for the treatment of different viral diseases. Just to highlight, Bavituximab has blockbuster potential in multiple therapeutic indications, it recognizes all enveloped viruses tested to date, it’s a non-mutatable target, it has a unique MOA, it works with the body’s own natural defenses to fight disease, and the novel MOA plus the non-mutatable target essentially make Bavituximab the ideal combination therapeutic.”
http://www.investorshub.com/boards/read_msg.asp?message_id=8289799

AND, STEVE KING MADE THIS INTERESTING COMMENT ON 7-14-06:
Question#3: Vertex’s drug used both, Ribavirin & Interferon. The J&J deal was one of the richest I’ve seen. How do you think our drug compares to Vertex’s drug?
SK: ”They’re difficult to compare – they have very diff. MOA’s, very diff. dosing regimens – they’ve really just very diff. drugs. Do I think we have the same potential as Vertex’s drug, well, of course I do. Given the facts of the long-lasting effects we’ve seen, the potential we’ve seen in pre-clinical studies – the potential is certainly there. Now we have to prove that out in clinical studies… We’re excited about the potential of Bavi, and who knows, maybe even in combo with Vertex’s drug.”
http://www.investorshub.com/boards/read_msg.asp?message_id=12052583

Ie,
VIRAL-REPLICATION-AGENT + IMMUNO-STIMULATORY AGENT = HCV-CONTROL

Now, let’s start filling in the blanks…

VIRAL-REPLICATION-AGENT. . .
. . .That’s curr. SOC Ribavirin, or future ‘direct-targeting’ agents like Telaprevir and Boceprevir or ??????.

IMMUNO-STIMULATORY AGENT. . .
. . .Is that to remain Interferon going forward, or does Bavi or YYYYY or ZZZZ enter the picture?

We do know that Interferon IS NOT too great, esp. when you factor in side-effects:
“A recent 14 day INTERFERON arm of a Schering Plough trial in previous relapsers, (PEG IFN alfa-2b alone), 22 patients, yielded an average .3 log10 viral reduction.”

Compare to the immuno-stimulatory agent Bavituximab:
11-5-07: “Ph.1B Results indicate that bavituximab was generally safe and well tolerated, with no dose limiting toxicities or serious adverse events reported. Anti-viral activity (decline of greater than or equal to .5 log10 reduction in HCV RNA) was observed at all dose levels and was most consistent in patients receiving 3 mg/kg of bavituximab. In this cohort, 83% of the patients demonstrated anti-viral activity. An assessment of the cytokine profile in this cohort also suggests bavituximab induces a pro-inflammatory cytokine profile, defined as an increase in the ratio of TNFalpha & TGFbeta. Stimulating an immune response is a key proposed anti-viral mechanism of action of bavituximab.”
As P.I. Dr. Eric Lawitz stated, "Future HepC therapy will likely require multiple mechanisms of action, including an immune modulating agent. Bavituximab has a novel targeted immunomodulatory mechanism and if proven effective, it has the potential to be complementary to emerging new anti-viral therapies for HCV infection."
11-5-07: Dr. Lawitz, Ph.1B data at AASLD’07 (Mono/Repeat-Dose, 24pts): http://tinyurl.com/3chefc

So far I’ve ID’d 5 novel “immune-modulator” drugs, in addition to Bavi, clearly being positioned as replacements for IFN in HCV Combo regimens - 4 now, since SCV-07 has been discontinued for HCV. I’m sure there are more – if you see them, pls. post and I’ll add to this list.

I. Idera’s IMO-2125 (TLR9 Agonist) - “being developed as a more effective & tolerable alternative to PEGylated IFN-a for administration in combination with ribavirin and direct-acting antiviral agents.”
http://www.dddmag.com/article-A-Novel-Immune-Modulator-for-the-Treatment-of-Hepatitis-C-12810.aspx

II. Novelos’ NOV-205 (‘Molixan’) - “a unique, injectable, small-molecule proprietary formulation of oxidized glutathione and inosine that acts as a hepatoprotective agent with immunomodulating and anti-inflammatory properties.”
http://www.hepctrust.org.uk/news/2010/April/Novelos+Starts+Phase+2+Trial+of+NOV-205+to+Reduce+Liver+Damage+in+Non-responders+to+Interferon+Thera

III. SciClone’s SCV-07 - “Broad Spectrum Immune Stimulator”. 12-16-10 Ph.2B, “was designed to evaluate the safety & immunomodulatory effects of SCV-07 as a monotherapy and in combination with ribavirin in relapsed HCV patients… SCV-07 was safe & well-tolerated… Topline results, however, showed that SCV-07 did not meet the study's primary efficacy endpoint, which was defined as a 2log red. in viral load from baseline level… SciClone has decided not to continue development in the HCV indication.”
http://investor.sciclone.com/releasedetail.cfm?ReleaseID=470147

IV. Santaris' SPC3649 (‘Miravirsen’) - “…many different small molecule antivirals are under development, but the problems with interferon remain. If successful, Santaris' SPC3649 may be able to replace it in anti-HCV cocktails.”
http://www.rsc.org/chemistryworld/News/2009/December/09120901.asp

V. Dynavax’ SD-101 - “utilizes a novel Type C TLR9 agonist based on our 2nd-gen. ISS… SD-101 is designed to be a potential replacement for interferon alpha therapy and be used in combination with oral antiviral therapy to stop HCV viral replication and induce a long-lasting immune response.”
http://www.wikinvest.com/stock/Dynavax_Technologies_(DVAX)/Sd-101%20Hepatitis%20Therapy

Excellent HCV Drug Dev. References:
http://www.medhelp.org/health_questions/ribavirin-mechanism-of-action
http://www.hcvdrugs.com
http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html

= = = = = = = Commentary on Market for HCV “Immuno-Stimulatory Agents”:
By: Fire Fox 1-11-11 2:34pm iHub #60001
You say "no revenue targets to digest." Try this one. Sales for SOC therapy in HCV in the U.S. are $4 billion. My understanding from a clinical doc is that Interferon represents half of the drug cost. We will know by early summer whether Bavi is on its way to replacing interferon in this $2 billion annual market. What would that do to the share price? Vertex is already trading at 40 times PPHM's market cap and they have just one of the several possible anti-viral drugs that must be used in combination with an immune stimulatory drug like interferon or Bavi. ...and this Vertex valuation analogy completely omits Bavi's massive anti-cancer potential…
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=58663300
Volume:
Day Range:
Bid:
Ask:
Last Trade Time:
Total Trades:
  • 1D
  • 1M
  • 3M
  • 6M
  • 1Y
  • 5Y
Recent CDMO News